Hair loss is a common problem which occurs, for example, through natural processes or is often chemically promoted through the use of certain therapeutic drugs designed to alleviate conditions such as cancer. Often such hair loss is accompanied by lack of hair regrowth which causes partial or full baldness. Such baldness is cosmetically unappealing, and is particularly distressing to the person experiencing the hair loss.
As is well-known in the art, hair growth occurs by a cycle of activity which involves alternating periods of growth and rest. This cycle is often divided into three main stages which are known as anagen, catagen, and telogen. Anagen is the growth phase of the cycle and may be characterized by penetration of the hair follicle deep into the dermis with rapid proliferation of cells which are differentiating to form hair. The next phase is catagen, which is a transitional stage marked by the cessation of cell division, and during which the hair follicle regresses through the dermis and hair growth is ceased. The next phase, telogen, is often characterized as the resting stage during which the regressed follicle contains a germ with tightly packed dermal papilla cells. At telogen, the initiation of a new anagen phase is caused by rapid cell proliferation in the germ, expansion of the dermal papilla, and elaboration of basement membrane components. This cycle is repeated throughout hair growth. Wherein hair growth ceases, most of the hair follicles reside in telogen and anagen is not engaged, thus causing the onset of full or partial baldness.
There have been many attempts in the literature to invoke the regrowth of hair by, for example, the promotion or prolongation of anagen. Currently, there are two drugs approved by the United States Food and Drug Administration for the treatment of male pattern baldness: topical minoxidil (marketed as Rogaine.RTM. by Pharmacia & Upjohn), and oral finasteride (marketed as Propecia.RTM. by Merck & Co., Inc.).
There are conflicting reports, however, regarding the ability of minoxidil to grow hair. In fact, early clinical studies investigating decreased blood pressure via the use of minoxidil did not even mention hypertrichosis (hair growth) as a side effect. See Dormois et al., "Minoxidil in Severe Hypertension: Value When Conventional Drugs Have Failed", American Heart Journal, Vol. 90, pp. 360-368 (1975). Indeed, the manufacturers of minoxidil have reported only limited hair growth in a portion of patients using minoxidil. See eg., Physician's Desk Reference.RTM., 49.sup.th Ed. (1995), p. 2580. Furthermore, serious side effects of minoxidil are possible, including vasodilation (which leads to retention of fluid around the heart and increased heart rate), difficulty in breathing, and weight gain. Physician's Desk Reference.RTM., 49.sup.th Ed. (1995), p. 2581.
Furthermore, while early indicators show that Propecia.RTM. may be more effective than Rogaine.RTM., patients using Propecia.RTM. are experiencing limited hair growth. See The New England Journal of Medicine, Vol. 338, No. 9, Feb. 26, 1998. Furthermore, potential side effects of Propecia.RTM. are serious. Propecia.RTM. may cause impotence, decreased sexual drive, decreased volume of ejaculate, breast tenderness and enlargement, and hypersensitivity reactions, including lip swelling and skin rash. Furthermore, Propecia.RTM. is not indicated for women and children. In fact, women who are pregnant or potentially pregnant should not even handle crushed or broken tablets containing the drug. See Physician's Desk Reference.RTM., 52.sup.th Ed. (1998), p. 1737 and The New England Journal of Medicine, Vol. 338, No. 9, Feb. 26, 1998.
Interestingly, the immunosuppressive agents cyclosporin A and FK506 are known to invoke a prominent hypertrichotic side effect. See Iwabuchi et al., "Effects of Immunosuppressive Peptidyl-Prolyl cis-trans Isomerase (PPIase) Inhibitors, Cyclosporin A, FK506, Ascomycin, and Rapamycin, on Hair Growth Initiation in Mouse: Immunosuppression is not Required for New Hair Growth", Journal of Dermatological Science, Vol. 9, pp. 64-69 (1995); Yamamoto et al., "Hair Growth-Stimulating Effects of Cyclosporin A and FK506, Potent Immunosuppressants", Journal of Dermatological Science, Vol. 7 (suppl.), pp. S47-S54 (1994); Yamamoto et al., "Stimulation of Hair Growth by Topical Application of FK506, a Potent Immunosuppressive Agent", Journal of Investigational Dermatology, Vol. 102, pp. 160-164 (1994); Jiang et al., "Induction of Anagen in Telogen Mouse Skin by Topical Application of FK506, a Potent Immunosuppressant", Journal of Investigational Dermatology, Vol. 104, pp. 523-525 (1995); McElwee et al., "Topical FK506: A Potent Immunotherapy for Alopecia Areata? Studies Using the Dundee Experimental Bald Rat Model", British Journal of Dermatology, Vol. 137, pp. 491-497 (1997); Maurer et al., "Hair Growth Modulation by Topical Immunophilin Ligands", American Journal of Pathology, Vol. 150, No. 4, pp. 1433-1441 (1997); and Paus et al., "Hair Growth Control by Immunosuppression", Arch. Dermatol. Res., Vol. 288, pp. 408-410 (1996). However, use of these compounds as hair growth actives may not be desirable due to their striking potency as immunosuppressive agents.
FK506 is a complex, macrocyclic molecule having the following structure: ##STR1##
Stocks et al., "The Contribution to Binding of the Pyranoside Substituents in the Excised Binding Domain of FK-506", Bioorganic & Medicinal Chemistry Letters, Vol. 4, No. 12, pp. 1457-1460 (1994). Analogs closely resembling this complex macrocycle have been disclosed as having hair growth properties in the form of, for example, alopecia areata and/or male pattern baldness. See, e.g., Kawai et al., U.S. Pat. No. 5,541,193, assigned to Abbott Laboratories, issued Jul. 30, 1996; Asakura et al., U.S. Pat. No. 5,496,564, assigned to Fujisawa Pharmaceutical Co., issued Mar. 5, 1996; Baumann et al., U.S. Pat. No. 5,352,671 assigned to Sandoz Ltd., issued Oct. 4, 1994; and Rupprecht et al., U.S. Pat. No. 5,550,233, assigned to Merck & Co., Inc., issued Aug. 27, 1996.
However, excitement related to the hypertrichotic activities of cyclosporin A and FK506 is somewhat quelled by the lack of reports of hypertrichosis by various smaller, non-macrocyclic immunosuppressive and non-immunosuppressive compounds which are less complex in structure than FK506. See Steiner et al., WO 96/40140, assigned to Guilford Pharmaceuticals, Inc., published Dec. 19, 1996; Hamilton et al., WO 96/40633, assigned to Guilford Pharmaceuticals, Inc., published Dec. 19, 1996; Steiner et al., U.S. Pat. No. 5,696,135, assigned to GPI NIL Holdings, Inc., issued Dec. 9, 1997; Hamilton et al., U.S. Pat. No. 5,614,547, assigned to Guilford Pharmaceuticals, Inc., issued Mar. 25, 1997; Steiner et al., WO 97/16190, assigned to Guilford Pharmaceuticals, Inc., published May 9, 1997; Zelle et al., WO 96/36630, assigned to Vertex Pharmaceuticals, Inc., published Nov. 21, 1996; Armistead et al., WO 97/36869, assigned to Vertex Pharmaceuticals, Inc., published Oct. 9, 1997; Zelle et al., WO 96/15101, assigned to Vertex Pharmaceuticals, Inc., published May 23, 1996; Armistead et al., WO 92/19593, assigned to Vertex Pharmaceuticals, Inc., published Nov. 12, 1992; Armistead et al., WO 94/07858, assigned to Vertex Pharmaceuticals, Inc., published Apr. 14, 1994; Zelle et al., WO 95/26337, assigned to Vertex Pharmaceuticals, Inc., published Oct. 5, 1995; Duffy et al., WO 92/21313, assigned to Vertex Pharmaceuticals, Inc., published Dec. 10, 1992; Armistead et al., U.S. Pat. No. 5,192,773, assigned to Vertex Pharmaceuticals, Inc., issued Mar. 9, 1993; Armistead et al., U.S. Pat. No. 5,330,993, assigned to Vertex Pharmaceuticals, Inc., issued Jul. 19, 1994; Armistead et al., U.S. Pat. No. 5,622,970, assigned to Vertex Pharmaceuticals, Inc., issued Apr. 22, 1997; Armistead et al., U.S. Pat. No. 5,654,332, assigned to Vertex Pharmaceuticals, Inc., issued Aug. 5, 1997; Armistead et al., U.S. Pat. No. 5,620,971, assigned to Vertex Pharmaceuticals, Inc., issued Apr. 15, 1997; Zelle et al., U.S. Pat. No. 5,543,423, assigned to Vertex Pharmaceuticals, Inc., issued Aug. 6, 1996; Armistead et al., U.S. Pat. No. 5,516,797, assigned to Vertex Pharmaceuticals, Inc., issued May 14, 1996; Armistead et al., U.S. Pat. No. 5,665,774, assigned to Vertex Pharmaceuticals, Inc., issued Sep. 9, 1997; Andres et al., "Conformationally Defined Analogs of Prolylamides. trans-Prolyl Peptidomimetics", Journal of Organic Chemistry, Vol. 58, pp. 6609-6613 (1993); and Armistead et al., "Design, Synthesis and Structure of Non-macrocyclic Inhibitors of FKBP12, the Major Binding Protein for the Immunosuppressant FK506", Acta Crystallographica, D51, pp. 522-528 (1995).
Surprisingly, the present inventors have discovered a novel class of compounds which arrest and/or reverse hair loss or promote hair growth but do not share the complex, macrocyclic structure of FK506. The present inventors have further discovered compounds among this novel class which invoke hair growth yet are surprisingly non-immunosuppressive or are nominally immunosuppressive. The minimized and/or absent immunosuppressive activity of these hypertrichotic compounds are distinct advantages as compared to the immunosuppressive compounds cyclosporin A and FK506.